Multiple myeloma (MM) is still incuable B-cell malignancy affecting more than 14,000 Americans annually. Myeloma tumor cells can survive even the most aggressive treatment available today, leading to disease relapses. The long-term goal of this project is to develop more effective cytostatic therapies to eradicate myeloma cells. We recently made a novel and exciting discovery that anti-[unreadable]2-microglobulin ([unreadable]2M) monoclonal antibodies (mAbs) had strong apoptotic activity in both established myeloma cell lines and primary myeloma cells from patients. The mAbs selectively target and kill myeloma cells in coculture with normal hematopoietic cells without damaging normal blood cells, including CD34+ stem cells in vitro, and were active and therapeutic in vivo in xenograft mouse models of myeloma. Anti-[unreadable]2M mAb-induced apoptosis in myeloma cells were not blocked by high concentrations of soluble [unreadable]2M, IL-6, or other myeloma growth and survival factors, and was stronger than apoptosis observed with chemotherapy drugs currently used to treat MM (e.g., dexamethasone). The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Moreover, we also showed that the mAbs may prevent or slowdown bone destruction in patients. Thus, we hypothesize that anti-[unreadable]2M mAbs may be used as therapeutic agents to treat patients with MM. This grant will elucidate the mechanisms of anti-[unreadable]2M mAb-mediated protection of myeloma bone disease. We will examine the in vitro effects and mechanism of anti-[unreadable]2M mAbs on myeloma and bone cells, and elucidate the mechanism of anti-[unreadable]2M mAb-mediated protection of bone diseases in vivo in myeloma SCID-hu model. These novel studies may lead to the development of anti-[unreadable]2M mAbs as the first clinically useful and effective therapeutic mAbs for the treatment of MM and potentially other malignancies that express surfacer than apoptosis observed with chemotherapy drugs currently used to treat MM (e.g., dexamethasone). The mAbs induced cell death via inhibiting PI3K/Akt and ERK, activating JNK, and compromising mitochondrial integrity, leading to cytochrome c release and activation of a caspase-9-dependent cascade. Moreover, we also showed that the mAbs may prevent or slowdown bone destruction in patients. Thus, we hypothesize that anti-[unreadable]2M mAbs may be used as therapeutic agents to treat patients with MM. This grant will elucidate the mechanisms of anti-[unreadable]2M mAb-mediated protection of myeloma bone disease. We will examine the in vitro effects and mechanism of anti-[unreadable]2M mAbs on myeloma and bone cells, and elucidate the mechanism of anti-[unreadable]2M mAb-mediated protection of bone diseases in vivo in myeloma SCID-hu model. These novel studies may lead to the development of anti-[unreadable]2M mAbs as the first clinically useful and effective therapeutic mAbs for the treatment of MM and potentially other malignancies that express surface [unreadable]2M and MHC class I molecules.